Prescription opioid non-medical use and abuse are a significant public health problem in this country. Epidemiological databases indicate that the problem has increased substantially since the late 1990s and currently shows no signs of abating. In our laboratory, we have studied abuse liability-related subjective effects of several oral opioids that are widely prescribed using an abuse liability testing methodology. Abuse liability-related subjective effects are effects that are considered pleasant in nature (e.g., euphoria, drug liking, feeling good) and have face validity in predicting abuse liability. Our volunteers are recreational drug users not meeting diagnostic criteria for drug abuse, a group that represents a large proportion of the general population. There appear to be differences between the prescription opioids we have tested in degree of abuse liability-related subjective effects, but rigorous, direct comparisons of these opioids within the same study and within the same individual have not been done. In the first series of studies proposed in this application, we will examine the relative abuse liability-related effects (testing both subjective and reinforcing effects) of prescription oral opioids by studying different doses of different opioids within the same study and within the same individual (Study 1: oxycodone versus hydrocodone; Study 2: oxycodone versus morphine). The second series of studies will identify potential risk factors for prescription opioid abuse. In our previous studies on prescription opioids, we have observed individual differences in the degree to which volunteers show abuse liability-related effects of an opioid. The fact that individual differences can be observed in our studies suggests that determinants of those differences can be studied in the laboratory, so that those variables that might lead to greater abuse liability-related effects of opioids can be identified. If a potential risk factor increases the abuse liability-related effects of a prescription opioid, it is likely that the risk factor contributes to the non-medical use and/or abuse of prescription opioids. The potential risk factors to be studied include organismic variables (anxiety disorder, sensation seeking), drug usage variables (light versus moderate ethanol usage) and pharmacological variables (ethanol). The studies in this application will continue to fill critical gaps in our knowledge base on the behavioral effects of prescription opioids, including relative abuse liability of different opioids, and potential risk factors that modulate the abuse liability-related effects of these drugs.